Empagliflozin is a SGLT-2 inhibitor with a chemical name (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-D-glucitol and has the following structural formula:
It was approved by the FDA in August, 2014 in the form of oral tablets for human use under the proprietary name, JARDIANCE® indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus; and to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established cardiovascular disease.
Dapagliflozin is an orally active SGLT-2 inhibitor, approved by the FDA in January, 2014 in the form of oral tablets for human use under the proprietary name, FARXIGA®. The active ingredient of the approved product is chemically designated as (1S)-1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl] phenyl]-D-glucitol, (2S)-propylene glycol monohydrate and is marketed for the treatment of type 2 diabetes mellitus. The empirical formula is C21H25ClO6.C3H8O2.H2O and the molecular weight is 502.98. The structural formula is:

Several methods are known in the art for the synthesis of SGLT-2 inhibitors.
PCT publication No. WO 2005/092877 discloses glucopyranosyl-substituted benzene derivative, (1S)-1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-D-glucitol (empagliflozin), and preparation process thereof, wherein 4-bromo-1-chloro-2-(4-methoxybenzyl)-benzene is reacted with boron tribromide (BBr3) in dichloromethane to produce 4-(5-bromo-2-chloro-benzyl)-phenol which is reacted with t-butyl dimethyl silyl chloride in dichloromethane in the presence of triethylamine and N,N-dimethylaminopyridine to get [4-(5-bromo-2-chloro-benzyl)-phenoxy]-tert-butyldimethylsilane which is further reacted with n-butyllithium in tetrahydrofuran (THF) followed by condensation with 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone. The resulting solution is reacted with methane sulfonic acid in methanol followed by reduction with triethylsilane and boron trifluoride etherate and acylated with acetic anhydride/pyridine in dichloromethane followed by treating with potassium hydroxide in methanol to produce phenolic intermediate. This phenolic intermediate is reacted with (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate to produce empagliflozin.
The above process involves the use of hazardous boron tribromide as it reacts violently and decomposes to toxic compounds when on contact with moisture.
International patent application, WO/2017/130217 describes a process for preparing empagliflozin, wherein the process for preparing 4-bromo-1-chloro-2-(4-methoxybenzyl)benzene comprises reducing (5-bromo-2-chlorophenyl)(4-methoxy phenyl)methanone using titanium tetrachloride and triethylsilane. Further, (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-hydroxybenzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate is treated with (R)-tetrahydrofuran-3-yl 4-nitrobenzenesulfonate in DMF, followed by deprotection to yield empagliflozin.
Titanium tetrachloride (TiCl4) is a strong Lewis acid, exothermically forming adducts with even weak bases such as THF and explosively with water and releasing HCl. (R)-tetrahydrofuran-3-yl-4-nitrobenzenesulfonate is not commercially available and its synthesis requires use of expensive starting materials, thereby increasing the raw material cost. This process may not be useful for economic production of empagliflozin.
International patent application, WO/2017/203457 discloses a process for preparing empagliflozin comprising reacting (R)-tetrahydrofuran-3-yl-4-methyl benzenesulfonate with (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol to yield empagliflozin.
However, the process for preparing compound (4-(2-chloro-5-iodobenzyl) phenoxy)(tert-butyl)dimethylsilane, involves multiple steps and makes use of expensive reagents such as 1,1,3,3-tetramethyldisiloxane (TMDS), tert-butyldimethylsilyl chloride (TBDMSCl) and use of cesium carbonate in preparing empagliflozin, thereby making it uneconomical.
U.S. Pat. Nos. 6,515,117; 7,375,213; 7,932,379; and 7,919,598 disclose processes for the preparation of dapagliflozin comprising the step of hydrolyzing an acetylated dapagliflozin, in the presence of an alkali metal hydroxide such as lithium hydroxide or sodium hydroxide to give pure dapagliflozin as an amorphous glassy off-white solid with a purity of 94%.
U.S. Pat. No. 8,952,139 discloses an alternate process for preparation of dapagliflozin by coupling 1,6-anhydro-2,4-di-O-tert-butyldiphenylsilyl-8-D-gluco pyranose with 4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl magnesium bromide to yield (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-3,5-bis(2,2-dimethyl-1,1-diphenylpropoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-4-ol followed by removal of protecting groups in tetrahydrofuran (THF) in the presence of TBAF and calcium carbonate to yield dapagliflozin.
Inefficiencies known in the art for preparing SGLT-2 inhibitors include (1) a lack of stereo selectivity during formation of the desired β-anomer of the C-arylglucoside, (2) relatively long synthetic routes (linear syntheses), (3) uneconomic protection of hydroxyl groups, (4) use of hazardous reagents, and/or (5) complex work-up procedures and (6) use of expensive raw materials.
Hence, there exists a continuous need for alternate, improved, safe and cost effective synthetic routes for the preparation of SGLT-2 inhibitors, with high chemical and enantiomeric purity, applicable for large scale production.
The present invention provides novel, improved processes which are convergent syntheses for the preparation of SGLT-2 inhibitors particularly empagliflozin and dapagliflozin, which are cost effective, non-hazardous, less cumbersome, advantageous over prior art, involving simplified work-up procedures with high yields, better enantiomeric purity and are commercially scalable in industry.